It is generally known to coat oral dosage forms, e.g. tablets or pellets, which comprise an acid-labile active ingredient, with an enteric coating which, after passing through the stomach, rapidly dissolves in the alkaline medium in the intestine. One example of such acid-labile active ingredients comprises acid-labile proton pump inhibitors (H+/K+-ATPase inhibitors), in particular pyridin-2-ylmethylsulfinyl-1H-benzimidazoles like those disclosed, for example, in EP-A-0 005 129, EP-A-0 166287, EP-A-0 174 726 and EP-A-0 268 956. Because of their H+/K+-ATPase-inhibiting effect, they are important in the therapy of disorders originating from increased gastric acid secretion. Examples of active ingredients from this group which are already commercially available are 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-1H-benzimidazole (INN: omeprazole), 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole (INN: pantoprazole), 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl)methylsulfinyl]-1H-benzimidazole (INN: lansoprazole) and 2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole (INN: rabeprazole).
Because of their great tendency to decompose in a neutral and, in particular, acidic environment, with production also of highly colored decomposition products, it is also necessary in this case for oral preparations to protect active ingredients from the effect of acids. With the very acid-labile pyridin-2-ylmethylsulfinyl-1H-benzimidazoles it is additionally necessary for them to be processed in the tablet core or in pellets in the form of their alkaline salts, for example as sodium salts, or together with alkaline substances. Since substances suitable for enteric coatings are those with free carboxyl groups, the problem arises that the enteric coating is, because of the alkaline medium in the interior, partially or even completely dissolved from inside, and the free carboxyl groups promote decomposition of the active ingredient. It is therefore necessary to provide a sealing intermediate layer (subcoating) between the enteric coating and the alkaline tablet core or pellet. EP-A-0 244 380 proposes that cores which contain the active ingredient together with alkaline compounds or as alkaline salt be coated with at least one layer which is soluble in water or rapidly disintegrates in water and is composed of nonacidic, inert pharmaceutically acceptable substances, before the enteric layer is applied. The intermediate layer or intermediate layers act as pH-buffering zones in which hydrogen ions diffusing in from outside are able to react with the hydroxyl ions diffusing out of the alkaline core. In order to increase the buffer capacity of the intermediate layer, it is proposed to incorporate buffer substances into the intermediate layer(s). By this process it is possible in practice to obtain reasonably stable preparations. However, relatively thick intermediate layers are required in order to avoid the unsightly discolorations which occur even with only slight decomposition. In addition, considerable effort must be invested to avoid traces of moisture during production.
The administration of solid dosage forms such as capsules or tablets proves to be problematic especially in animals or patients who have difficulties with swallowing, such as, for example, elderly people and small children.
WO94/25070 describes an oral pharmaceutical preparation comprising a proton pump inhibitor in the form of a paste for treating acid-related gastric disorders in animals. For this purpose, enteric coated particles (such as tablets or beads) which comprise a proton pump inhibitor either are mixed with dry gelling agents, and this mixture is then mixed with water immediately before administration, or the enteric particles are mixed with potassium or calcium salts and mixed immediately before administration with a low-viscosity solution of a polymeric gel-forming agent. An alternative proposal is to mix enteric coated particles immediately before administration with a low-viscosity solution of a gel-forming agent in the form of a temperature-sensitive polymer, and to heat the solution cautiously. The preparations described herein have the disadvantage for the user, however, that the paste must be prepared immediately before administration.
U.S. Pat. No. 5,708,017 and WO00/50038 describe an oral pharmaceutical preparation which is ready for use and comprises omeprazole in the form of a paste for treating acid-related gastric disorders in humans and animals. This preparation in paste form comprises omeprazole, basifying agents, a thickener and a hydrophobic, oily liquid vehicle. The hydrophobic oily liquid vehicle comprises a vegetable oil and tri-glycerides of medium chain length fatty acids or propylene glycol diesters of medium chain length fatty acids. According to WO00/50038, these preparations are stable and can be used to fill syringes which can then be used directly for administering the active ingredient to an animal.